Polymer micelles have been used widely for delivery of poorly water-soluble drugs. Despite their promising properties, they have not been fully developed as a vehicle for target delivery of anticancer agents. This is mainly due to the lack of understanding on the in vivo behavior of polymer micelles upon intravenous administration. Physically self-assembled polymer micelles are not expected to be stable in blood, and yet, no systematic studies have been made. This study is focused on understanding the interactions between polymer micelles and blood components for development of a new class of polymer micelles for targeted delivery of anticancer agents for clinical applications. The long-term goal of this research is to develop adaptable polymer micelles that are stable in blood but undergo dissociation by enzymes abundant at the tumor site. The hypothesis in this project is that the stability of polymer micelles in blood is prerequisite for successful tumor therapy. Only the stable polymer micelles have chances to target tumors and deliver anti-tumoral drugs at the therapeutically effective level. Specific Aims of this project are: (1) to develop adaptable polymer micelles; (2) to examine the micelle stability in blood; (3) to elucidate the micelle-cell interactions; and (4) to characterize the in vivo fate of micelles and to study the anti-tumoral activity of drug-loaded micelles. The two drugs to be used for tumor therapy are paclitaxel and gefitinib, which have similar hydrophobicity. The synergistic effect of the two-drug pair is expected, resulting in substantially better anti-tumoral effect. The adaptable polymer micelles will be prepared by crosslinking the hydrophobic core of the micelles through disulfide or peptides that are degradable by thrombin or matrix metalloproteinase 2 (MMP2) which are abundant at the tumor sites. The blood stability and tumor targeting properties of the adaptable polymer micelles will be examined by coherent anti-Stokes Raman scattering (CARS), fluorescence reflectance imaging (FRI), and fluorescence molecular tomography (FMT). The results of in vitro and in vivo experiments will be used to improve the properties of the adaptable polymer micelles, and such feedback cycle will be repeated to produce the optimal polymer micelles. The significance of our proposed research is that it will elucidate the factors affecting the stability of polymer micelles in blood, as well as cellular uptake, and in vivo fate/behavior of the micelles. Successful completion of this project is expected to produce adaptable polymer micelles that are effective for targeted delivery of a two-drug pair to the tumor sites.